Dhawan Punita, Su Yingjun, Thu Yee Mon, Yu Yingchun, Baugher Paige, Ellis Darrel L, Sobolik-Delmaire Tammy, Kelley Mark, Cheung Timothy C, Ware Carl F, Richmond Ann
Department of Veterans Affairs, Nashville, TN 37212, USA.
J Biol Chem. 2008 May 30;283(22):15399-408. doi: 10.1074/jbc.M708272200. Epub 2008 Mar 17.
The pleiotropic transcription factor nuclear factor-kappaB (NF-kappaB (p50/p65)) regulates the transcription of genes involved in the modulation of cell proliferation, apoptosis, and oncogenesis. Furthermore, a host of solid and hematopoietic tumor types exhibit constitutive activation of NF-kappaB (Basseres, D. S., and Baldwin, A. S. (2006) 25, 6817-6830). However, the mechanism for this constitutive activation of NF-kappaB has not been elucidated in the tumors. We have previously shown that NF-kappaB-inducing kinase (NIK) protein and its association with Inhibitor of kappaB kinase alphabeta are elevated in melanoma cells compared with their normal counterpart, leading to constitutive activation of NF-kappaB. Moreover, expression of dominant negative NIK blocked this base-line NF-kappaB activity in melanoma cells. Of the three receptors that require NIK for activation of NF-kappaB, only the lymphotoxin-beta receptor (LTbeta-R) is expressed in melanoma. We show in this manuscript that for melanoma there is a strong relationship between expression of the LTbeta-R and constitutive NF-kappaB transcriptional activity. Moreover, we show that activation of the LTbeta-R can drive NF-kappaB activity to regulate gene expression that leads to enhanced cell growth. The inhibition by LTbeta-R shRNA resulted in decreased NF-kappaB promoter activity, decreased growth, and decreased invasiveness as compared with control. These results indicate that the LTbeta-R constitutively induces NF-kappaB activation, and this event may be associated with autonomous growth of melanoma cells.
多效转录因子核因子-κB（NF-κB（p50/p65））调节参与细胞增殖、凋亡和肿瘤发生调控的基因转录。此外，许多实体瘤和血液肿瘤类型均表现出NF-κB的组成性激活（Basseres, D. S., and Baldwin, A. S. (2006) 25, 6817 - 6830）。然而，肿瘤中NF-κB这种组成性激活的机制尚未阐明。我们之前已经表明，与正常对应物相比，黑色素瘤细胞中NF-κB诱导激酶（NIK）蛋白及其与κB激酶αβ抑制剂的结合升高，导致NF-κB的组成性激活。此外，显性负性NIK的表达阻断了黑色素瘤细胞中的这种基线NF-κB活性。在激活NF-κB需要NIK的三种受体中，只有淋巴毒素-β受体（LTβ-R）在黑色素瘤中表达。我们在本论文中表明，对于黑色素瘤，LTβ-R的表达与组成性NF-κB转录活性之间存在密切关系。此外，我们表明LTβ-R的激活可驱动NF-κB活性以调节导致细胞生长增强的基因表达。与对照相比，LTβ-R shRNA的抑制导致NF-κB启动子活性降低、生长减少和侵袭性降低。这些结果表明，LTβ-R组成性诱导NF-κB激活，并且这一事件可能与黑色素瘤细胞的自主生长有关。
